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PubMed1991

Pharmacologic profile of a new anxiolytic, DN-2327: effect of Ro15-1788 and interaction with diazepam in rodents.

In order to characterize the pharmacologic profile of DN-2327, an isoindoline benzodiazepine (BZD) receptor ligand, its interactions with Ro15-1788 and diazepam were analyzed in rodents. The anti-conflict action of DN-2327 in two conflict tests using rats, the punished water-lick conflict (Vogel conflict) and the punished bar-pressing conflict test, was completely attenuated by treatment with Ro15-1788. The anti-convulsive (pentylenetetrazol [PTZ] induced convulsion) effect of DN-2327 was also reduced by Ro15-1788. These results suggest that the anti-conflict and anti-convulsive actions of DN-2327 may be mediated via BZD receptors. On the other hand, DN-2327 only slightly affected the motor coordination in mice and rats, as estimated by the inclined screen test and the climbing test, respectively; however, the compound attenuated the motor incoordination produced by diazepam. Furthermore, the pentobarbital potentiating effect of diazepam was reduced by pretreatment with DN-2327 in mice. In the Vogel conflict test, additive effects were observed upon the conflict test, additive effects were observed upon the concomitant administration of subeffective doses (5 mg/kg, PO) of DN-2327 and diazepam. DN-2327 at 20 mg/kg, PO, did not reduce but slightly potentiated the anti-conflict effect of the maximum effective dose of diazepam. For PTZ-induced convulsions, DN-2327, 0.5 and 20 mg/kg, PO, doses which produced partial and complete anti-convulsive effects, respectively, in rats did not reduce but increased additively the effects of diazepam. DN-2327 at 10 and 20 mg/kg, PO, doses which both produced partial anti-convulsive effects in mice, showed an additive effect with the partial effects of diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Suppression of alcohol and saccharin preference in rats by a novel Ca2+ channel inhibitor, Goe 5438.

The effect of the novel 1,4-dihydronaphthyridine Ca2+ channel inhibitor Goe 5438 (CI-951) on voluntary ethanol consumption was examined in selectively bred alcohol-preferring (P) rats in a free choice two bottle preference test versus water. Intraperitoneally injected Goe 5438 dose-dependently (5, 10 or 20 mumol/kg, twice daily) inhibited ethanol and increased water intake over the 24 h period (injection day). The drug decreased ethanol preference, originally above 90%, by 6%, 19% and 45% at respective doses, on the injection day. That inhibitory effect of the highest dose of Goe 5438 on ethanol preference remained significant also on days 2 and 3 after injections (-51% and -18%, respectively). Goe 5438, in the highest dose, also tended to decrease granulated chow consumption during the injection day only. To further test whether the inhibition of ethanol preference is secondary to decrease in reinforcing properties of ethanol and not due to interference with satiety mechanisms, we compared the effect of two higher doses (10 and 20 mumol/kg, intraperitoneally, twice daily) of Goe 5438 on spontaneous preference for a non-caloric 0.04% saccharin solution in Sprague-Dawley rats. We observed a dose-dependent suppression of preference (by 44% and 58%, respectively) during the injection day, but not the subsequent 24 h period. However, Goe 5438 also significantly alleviated food pellet intake on the injection day. In conclusion, Goe 5438 produces potent and long-lasting inhibition of voluntary ethanol consumption, which may be secondary to attenuation of reinforcing properties of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1994

Evaluating the effects of an alpha-2 adrenoceptor antagonist on erectile function in the human male. 1. The erectile response to erotic stimuli in volunteers.

The effects of a new alpha-2 adrenoceptor antagonist on erectile function was assessed in 12 normal volunteers (mean age 28.7, range 20-42), using a double blind, placebo controlled design with two doses of drug and three testing sessions. The drug was administered by intravenous infusion and erectile responses to erotic fantasy and films were monitored by a Rigiscan device. Four effects of the drug were observed; (i) an increase in spontaneous erections; (ii) increased subjective ratings of sexual arousal, before presentation of erotic stimuli; (iii) increased duration of erectile response to erotic stimuli; and (iv) increases in systolic BP and HR both before and during erotic stimulation. These effects were largely restricted to the high dose of the drug. Adverse effects of the drug were minimal.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1994

Evaluating the effects of an alpha-2 adrenoceptor antagonist on erectile function in the human male. 2. The erectile response to erotic stimuli in men with erectile dysfunction, in relation to age and in comparison with normal volunteers.

The effect of a new alpha-2 adrenoceptor antagonist on erectile function was assessed in 24 men with probable psychogenic erectile dysfunction. The drug was given in two dosages, together with placebo, by intravenous infusion in a balanced cross over design. Once plasma levels were established, erectile, subjective and haemodynamic responses to erotic fantasy and films were measured. Subjects were divided into two age groups, "Younger" (i.e. less than 45 years) and "Older" (greater than 45 years). There was a significant though modest increase in the duration of erectile response with the high dose of the drug, but only in the younger men. There were also drug effects on haemodynamic responses confined to the younger men, who showed markedly reduced responses during placebo administration when compared with the older dysfunctional men and with young "functional" volunteers. The findings raise the possibility that in younger men with psychogenic erectile failure, there is an inhibition of general arousal responses to erotic stimuli which is partially reversed by this drug. In the older men, the different pattern of response suggests that a) there may be a decline in response to the drug with age and b) other age-related factors are playing an important part in the aetiology of their erectile failure.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1991

Controlled comparison of the efficacy and safety of four doses of suriclone, diazepam, and placebo in generalized anxiety disorder.

The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2, 0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared in six parallel groups of 54-59 outpatients with generalized anxiety disorder (DSM III-R). After a 1-week placebo run-in period, the patients were treated for 4 weeks, with assessments at baseline and after 1, 2, and 4 weeks by the Hamilton anxiety scale and the Clinical Global Impressions. Results showed better improvement with active drugs as compared to placebo, without significant differences among the four different doses of suriclone and diazepam. The number of adverse events, particularly drowsiness, was significantly higher with diazepam than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ from placebo. These results demonstrate that suriclone at daily doses ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated than diazepam.

Adolescent↗
PubMed1991

Effects of DN-2327, a new anxiolytic, diazepam and buspirone on exploratory activity of the rat in an elevated plus-maze.

In the present study, the effects of a new anxiolytic, DN-2327, were compared to those of diazepam and buspirone in rats in the elevated plus-maze test. Two indices of anxiety were obtained in this test: the number of entries into the open arms expressed as a percentage of the total number of arm entries and the percentage of time spent on the open arms. Both a typical anxiolytic, diazepam, at 2.5, 5 and 10 mg/kg, PO and a new anxiolytic, DN-2327, at 2.5 and 5 mg/kg, PO dose-dependently increased the two indices: the percentage of time spent on the open arms and the percentage of open-arm entries. On the other hand, pentylenetetrazol (PTZ) at 10 and 20 mg/kg, IP decreased the two indices dose dependently as did yohimbine at 1.5 and 3 mg/kg, IP. DN-2327 at 2.5 and 5 mg/kg, PO and diazepam at 5 and 10 mg/kg, PO dose dependently and significantly increased the two indices that were suppressed following administration of PTZ at 10 mg/kg, IP. The effects of both DN-2327, 5 mg/kg, PO, and diazepam, 10 mg/kg, PO, on the two indices were significantly antagonized by the benzodiazepine (BZD) receptor antagonist flumazenil, 20 mg/kg, IP. Buspirone (2.5-20 mg/kg, PO) did not affect either of the two responses but dose dependently decreased the number of rearings, although in the Vogel conflict test, the anti-conflict activity of buspirone was equipotent to that of diazepam and DN-2327 at the minimum effective dose (10 mg/kg, PO) of each drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

A comparative study of the psychological effects of DN-2327, a partial benzodiazepine agonist, and alprazolam.

The effects of single oral doses of DN-2327 (DN, 2 mg or 3 mg), a newly developed partial benzodiazepine receptor agonist, and alprazolam (APZ, 0.8 mg), a full receptor agonist, on psychomotor function and short-term memory were assessed using three psychometric tests: letter cancellation, visual vigilance and Sternberg's memory scanning task. Twelve healthy male volunteers participated in this study. Randomized, double-blind, cross-over test sessions were conducted at 2-week intervals. Both 3 mg DN and 0.8 mg APZ increased the time to completion of the letter cancellation task at 3 h after administration, but neither had any effect on accuracy of response. In the visual vigilance task, which required relatively intense concentration and continuous attention, both the number of errors and reaction times to correct responses significantly increased from 1.5 to 3.5 h after administration of 3 mg DN and at 3.5 h after administration with 0.8 mg APZ. DN at 2 mg also significantly increased the number of errors from 1.5 to 3.5 h after administration, but it did not affect reaction times. In the memory scanning task, 3 mg DN, but not 2 mg DN or APZ, significantly increased overall reaction times at 2 h after administration. These performance deficits paralleled the time-course changes in serum concentrations of both drugs and appeared to be associated with the hypnotic-sedative effects of the drugs tested. These findings did not support those of previous preclinical studies of DN, indicating superiority of DN over conventional full benzodiazepine agonists/anxiolytics in terms of adverse behavioral consequences.

Adult↗
PubMed1993

Discriminative stimulus properties of a new anxiolytic, DN-2327, in rats.

In an operant learning lever-pressing procedure on an FR10 schedule of milk reinforcement, male Wistar rats were trained to discriminate between saline and 3 mg/kg IP DN-2327, a new anxiolytic which acts on benzodiazepine receptors, 3 mg/kg IP diazepam or 15 mg/kg IP pentylenetetrazol (PTZ). More than 80% appropriate lever responding was established after 27, 38 and 44 daily training sessions with DN-2327, diazepam and PTZ, respectively, as the training drug. Although rats trained with DN-2327 dose-dependently generalized to various doses of DN-2327 and diazepam, the cue of DN-2327 was more potent than that of diazepam: ED50 values of DN-2327 and diazepam for stimulus generalization were 0.30 and 0.66 mg/kg, respectively. These animals partially generalized to pentobarbital (1-10 mg/kg) but did not generalize to buspirone (0.1-10 mg/kg). Rats trained with diazepam dose-dependently generalized to various doses of DN-2327, diazepam and pentobarbital with ED50 values of 0.51, 0.47 and 4.5 mg/kg, respectively, but did not generalize to buspirone. In rats trained with PTZ, DN-2327 and diazepam antagonized the discriminative stimulus produced by 15 mg/kg PTZ in a dose-dependent manner with ED50 values of 0.27 and 0.83 mg/kg, respectively, but buspirone neither antagonized nor was able to substitute for the PTZ-induced stimulus. The cue of DN-2327 was antagonized by flumazenil dose-dependently as was that of diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Comparative antimicrobial activity and spectrum of CP-99,219, a novel fluoroquinolone, tested against ciprofloxacin-resistant clinical isolates.

The fluoroquinolones have an established role in treatment of infection with aerobic gram negative rods. The increased importance of gram positive nosocomial infection and of acquired fluoroquinolone resistance has stimulated a search for new compounds with enhanced potency and spectrum. CP-99,219 is a novel compound in this class with enhanced activity against gram positive organisms. We have studied the activity of CP-99,219 relative to ciprofloxacin, fleroxacin, ofloxacin, and sparfloxacin using test panels of organisms with a high proportion of ciprofloxacin resistance. CP-99,219 is more potent than any of the other four compounds against both gram positive and gram negative bacteria. The activity of CP-99,219 against many bacteria resistant to the established agents, warrants further in vitro and clinical studies.

Acinetobacter↗
PubMed2001

In vitro activity of gemifloxacin (SB-265805) compared to eleven other antimicrobial agents against streptococcal isolates, excluding Streptococcus pneumoniae.

The purpose of the study presented here was to determine the in vitro activity of gemifloxacin compared with that of 11 other antimicrobial agents (5 of them quinolones) against 400 isolates of beta-haemolytic and viridans group streptococci. The minimum inhibitory concentration values for gemifloxacin against 90% of the streptococci tested were as follows: Lancefield groups A, C and G, 0.06 microg/ml; Lancefield group B, Streptococcus mitis, Streptococcus mutans and Streptococcus bovis, 0.125 microg/ml; and Streptococcus milleri, 0.03 microg/ml. Resistance to penicillin, ampicillin and erythromycin was found mainly in the Streptococcus mitis isolates; tetracycline showed variable results, and no vancomycin resistance was encountered. Higher rates of ciprofloxacin resistance were identified in the Streptococcus bovis, mitis and mutans isolates. In conclusion, gemifloxacin was the most active quinolone tested followed by trovafloxacin, sparfloxacin, grepafloxacin, ciprofloxacin and levofloxacin, especially against isolates resistant to beta-lactam agents, macrolides and tetracycline.

Anti-Bacterial Agents↗
PubMed2004

KF19514, a phosphodiesterase 4 and 1 inhibitor, inhibits TNF-alpha-induced GM-CSF production by a human bronchial epithelial cell line via inhibition of PDE4.

OBJECTIVE AND DESIGN: Bronchial epithelium plays an important role in the regulation of inflammatory reactions in the airways. We investigated the effect of KF19514, a phosphodiesterase (PDE) 4 and 1 inhibitor, on granulocyte-macrophage colony-stimulating factor (GM-CSF) production by a human bronchial epithelial cell line, BEAS-2B. METHODS: BEAS-2B cells were stimulated with the tumor necrosis factor-alpha (TNF-alpha) and various concentrations of test agents for 48 h. Supernatants were assayed for GM-CSF by using an enzyme-linked immunosorbent assay (ELISA). In addition, intracellular cyclic AMP (cAMP) levels were measured in the presence of various agents. RESULTS: KF19514 significantly inhibited the release of GM-CSF by BEAS-2B cells in a concentration-dependent manner. The other PDE4 inhibitors and cAMP-elevating agents also inhibited the GM-CSF production. In the BEAS-2B cells, KF19514 and PDE4 inhibitors concentration-dependently increased intracellular cAMP levels. The inhibitory effect of KF19514 on the GM-CSF production was significantly reduced by a cAMP-dependent protein kinase A (PKA) inhibitor, H89. On the other hand, other PDE isozyme inhibitors did not inhibit the GM-CSF production by BEAS-2B cells, and did not elevate the intracellular cAMP levels. CONCLUSIONS: These results indicate that KF19514 and PDE4 inhibitors reduce TNF-alpha-induced GM-CSF production of BEAS-2B cells via a cAMP-dependent pathway. PDE4 may be a possible target for the regulation of cytokine production in epithelial cells.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Effects of fluoroquinolones on the locomotor activity in rats.

During therapy with fluoroquinolones adverse CNS reactions such as dizziness, light-headedness, insomnia or sleepiness are observed in up to 20% of patients. Using a device developed at our institute for the simultaneous registration of the activity of rats housed in single cages, we have investigated the effects of trovafloxacin, fleroxacin or ofloxacin on the locomotor activity of juvenile and adult rats (11 per group) after oral administration of 600 mg/kg for 5 consecutive days. The effects were most pronounced after fleroxacin, which induced a reduction in activity to 36 +/- 9% (mean +/- SD) of the values measured in juvenile rats before treatment and to 60 +/- 21% (mean +/- SD) in adult rats. HPLC analysis of the plasma concentrations in juvenile rats showed that the concentrations of trovafloxacin were considerably lower than those of the other fluoroquinolones that had been studied previously in our laboratory: the peak concentration of trovafloxacin was 14 +/- 2.9 mg/l (mean +/- SD) after a single dose of 600 mg/kg in juvenile rats. Overall, we showed that the locomotor activities of juvenile and adult rats were significantly depressed during treatment with fluoroquinolones. The effects were more pronounced in juveniles. Monitoring of the locomotor activity of rats is a suitable approach to study CNS effects of fluoroquinolones in animals, but pharmacokinetics have to be taken into account.

Administration, Oral↗
PubMed2001

Effects of centrally administered orexin-B and orexin-A: a role for orexin-1 receptors in orexin-B-induced hyperactivity.

RATIONALE: Orexin-A and orexin-B are hypothalamic neuropeptides derived from a 130-amino acid precursor, prepro-orexin, and are potent agonists at both the orexin-1 (OX1) and orexin-2 (OX2) receptors. Orexin-A has been ascribed a number of in vivo functions in the rat after intracerebroventricular (ICV) administration, including hyperphagia, neuroendocrine modulation and a role in the regulation of sleep-wake function. The in vivo role of orexin-B is not as clear. OBJECTIVES: To investigate the behavioural, endocrine and neurochemical effects of orexin-B in in-vivo tests. In a number of experiments, these effects were compared with those of orexin-A. METHODS: Experiments were carried out in male, Sprague-Dawley rats with a guide cannula directed towards the lateral ventricle. The effects of orexin-B (ICV) upon grooming behaviour were compared with those of orexin-A. The effects of orexin-B upon the motor activity response to both novel and familiar environments were assessed in an automated activity monitor. Orexin-B was tested upon startle reactivity and body temperature. Further, plasma hormones and [DOPAC+ HVA]/[DA] and [5-HIAA]/[5-HT] ratios in six brain areas were measured 40 min post-orexin-B or orexin-A. RESULTS: The clearest behavioural response to orexin-B was increased motor activity in both novel and familiar environments. Orexin-B-induced hyperactivity was blocked by an OX1 receptor antagonist, SB-334867-A, implicating OX1 receptors in this behavioural response. In common with orexin-A, orexin-B reduced plasma prolactin and failed to influence startle reactivity. However, in contrast with orexin-A, orexin-B increased head grooming but failed to cause a robust whole body grooming response or increase plasma corticosterone levels. Further, orexin-B, but not orexin-A, increased plasma TSH and increased hypothalamic and striatal [5-HIAA]/[5-HT] ratios. CONCLUSIONS: The present study has demonstrated a number of behavioural, neuroendocrine and neurochemical effects of orexin-B that distinguish it from orexin-A. Further, we have demonstrated a role for OX1 receptors in the actions of orexin-B upon motor activity.

Animals↗
PubMed2001

The differential effects of prenatal stress in rats on the acoustic startle reflex under baseline conditions and in response to anxiogenic drugs.

RATIONALE: The prenatal stress syndrome (PS) is characterized by exaggerated behavioral and physiological responses to stressful stimuli and anxiogenic agents. OBJECTIVES: To characterize the behavioral effects of PS on the acoustic startle reflex (ASR) and to determine the possible role of PS-induced alterations in noradrenergic control of ASR by determining the effects of the alpha2-adrenoceptor antagonists, yohimbine, idazoxan, and RS79948-197. METHODS: PS was induced by exposing pregnant dams to a mild stressor of handling and saline injection (0.1 ml, s.c.) from gestational days 14 to 21. Control dams were left undisturbed throughout pregnancy. Using adult male offspring, all ASR studies consisted of either a 30- or 60-min testing period containing 60 or 120 acoustic startle stimuli trials (95 dB, 50 ms noise burst) at a fixed intertrial interval of 30 s after a 5-min acclimation period. For drug studies, a 3-day repeated measures design was implemented. RESULTS: With the exception of the response to the first startle stimulus on the first day of testing, there were no significant differences in baseline ASR between control and PS offspring. Low doses of yohimbine, idazoxan, and RS79948-197 were anxiogenic in the ASR test in both control and PS offspring. PS offspring were less responsive to higher doses of yohimbine (5 mg/kg) and idazoxan (8 mg/kg) but did not differ from control in their responses to any dose of RS79948-197. CONCLUSIONS: Anxiogenic effects of yohimbine, idazoxan, and RS79978-197, likely mediated via alpha2-adrenoceptor blockade, are similar in control and PS rats. Differences between control and PS rats occurred in the response to higher doses of yohimbine and idazoxan. Non-specific effects of these drugs, such as actions at 5HT1A receptors, may cause their behavioral profile to be altered by PS, and to differ from the highly selective RS79948-197.

Adrenergic alpha-Antagonists↗
PubMed2000

Evaluation of [O-methyl-11C]RS-15385-197 as a positron emission tomography radioligand for central alpha2-adrenoceptors.

Carbon-11 labelled RS-15385-197 and its ethylsulphonyl analogue, RS-79948-197, were evaluated in rats as potential radioligands to image central alpha2-adrenoceptors in vivo. The biodistributions of both compounds were comparable with that obtained in an earlier study using tritiated RS-79948-197 and were consistent with the known localisation of alpha2-adrenoceptors. The maximal signals (total to non-specific binding) were, however, reduced, in the order [11C]RS-79948-197 < [11C]RS-15385-197 < [3H]RS-79948-197, primarily due to the difference in radiolabel position (O-methyl for carbon- 11 compared with S-ethyl for tritium). This resulted in the in-growth of radiolabelled metabolites in plasma, which, in turn, contributed to the non-specific component of brain radioactivity. Nonetheless, the signal ratio of approximately 5 for a receptor-dense tissue compared with the receptor-sparse cerebellum, at 90-120 min after radioligand injection, encouraged the development of [O-methyl-11C]RS-15385-197 for human positron emission tomography (PET). Unfortunately, in two human PET scans (each of 90 min), brain extraction of the radioligand was minimal, with volumes of distribution more than an order of magnitude lower than that measured in rats. Following intravenous injection, radioactivity was retained in plasma and metabolism of the radiolabelled compound was very low. Retrospective measurements of in vitro plasma protein binding and in vivo brain uptake index (BUI) in rats demonstrated a higher protein binding of the radioligand in human compared with rat plasma and a lower BUI in the presence of human plasma. It is feasible that a higher affinity of RS-15385-197 for human plasma protein compared with receptor limited the transport of the radioligand. Although one of the PET scans showed a slight heterogeneity in biodistribution of radioactivity which was consistent with the known localisation of alpha2-adrenoceptors in human brain, it was concluded that [O-methyl-11C]RS-15385-197 showed little promise for routine quantification of alpha2-adrenoceptors in man.

Adult↗
PubMed2006

Systemic and renal hemodynamic effects of the AT1 receptor antagonist, ZD 7155, and the AT2 receptor antagonist, PD 123319, in conscious lambs.

Experiments were carried out to investigate age- and dose-dependent effects of the selective AT(1) receptor antagonist, ZD 7155, and the selective AT(2) receptor antagonist, PD 123319, on systemic and renal hemodynamics in conscious, chronically instrumented lambs aged approximately 1 and approximately 6 weeks of postnatal life. Mean arterial pressure (MAP), mean venous pressure (MVP), and renal blood flow (RBF) were measured for 10 min before and for 120 min after ZD 7155, PD 123319, or vehicle. In both age groups, administration of ZD 7155 decreased renal vascular resistance (RVR) and increased RBF within 5 min. These responses lasted less than 90 min but were not dose-dependent. MAP decreased by 30 min after administration of ZD 7155 in both age groups at doses >/=400 microg kg(-1); the remaining decreased for up to 120 min, depending upon the dose. Pressor responses to angiotensin II (ANG II) were abolished within 5 min of administration of all doses of ZD 7155, at both 1- and 6 weeks. PD 123319 had no detectable effects on systemic or renal hemodynamics or on the pressor responses to ANG II. Therefore, under physiological conditions in conscious newborn animals, ANG II modulates both resting blood pressure and RVR through activation of AT(1) but not AT(2) receptors.

Angiotensin II↗